Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tobacco and mainstream smoke of 20 commercial brands of filter and non-filter cigarettes were analysed for N-nitroso compounds. The concentrations of N-nitrosodimethylamine (NDMA), N-nitrosoethylmethylamine (NEMA) and N-nitrosopyrrolidine (NPYR) in cigarette tobacco were very much lower than in mainstream smoke, where the levels were 6.3-76.4 ng/cig NDMA, less than 1.0-7.1 ng/cig NEMA and 3.9-41.2 ng/cig NPYR. N-Nitrosodiethylamine was not detected in mainstream smoke and N-nitrosopiperidine (less than 1.0 ng/cig) was detected in the smoke of four unfiltered cigarette brands. The five major non-volatile nitrosamines present in cigarette tobacco were 4-(N-nitroso-N-methylamino)butyric acid (not detected to 200 ng/cig), N-nitrosopipecolic acid (not detected to 670 ng/cig), N-nitrososarcosine (22-460 ng/cig), 3-(N-nitroso-N-methylamino)propionic acid (110-4990 ng/cig) and N-nitrosoproline (580-15000 ng/cig). The tobacco-specific nitrosamines N-nitrosoanabasine and N-nitrosoanatabine were found at levels of 270-2330 ng/cig and 18-205 ng/cig in cigarette tobacco and mainstream smoke respectively. N-Nitrosonornicotine was present at 400-5340 ng/cig and 19-855 ng/cig in cigarette tobacco and mainstream smoke respectively. 4-(N-Nitrosomethyl-amino)-1-(3-pyridyl)-1-butanone concentrations of 100-960 ng/cig and 21-470 ng/cig in cigarette tobacco and mainstream smoke were determined. 4-(N-Nitrosomethyl-amino)-4-(3-pyridyl)-1-butanol (iso-NNAL) was detected in four dark (French) tobacco unfiltered cigarettes at a concentration range of 140-240 ng/cig and 5-11 ng/cig in the corresponding mainstream smoke. For non-filter cigarettes, a transfer rate of 3.4-4.6% for iso-NNAL was calculated.
Carcinogenesis 1991 Feb
PMID:N-nitroso compounds in cigarette tobacco and their occurrence in mainstream tobacco smoke. 199 91

Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.
Carcinogenesis 1991 May
PMID:Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses. 202 39

Dose-dependent development of pre-neoplastic liver cell foci induced by 2-acetylaminofluorene (2-AAF) was investigated in relation to cell-proliferative activity. Male F344 rats were initially given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and starting 2 weeks later received diets containing 2-AAF at dose levels of 150, 100, 60, 45, 35 or 30 p.p.m., 500 p.p.m. phenobarbital (PB) or basal diet as a control for 6 weeks. Two-thirds partial hepatectomy (PH) was performed at week 3. The rats were sequentially killed from weeks 0 to 16 and liver sections were analysed by double staining for both BrdU incorporation and glutathione S-transferase placental form (GST-P) expression. 2-AAF increased numbers and areas of GST-P positive (GST-P+) foci in a dose-dependent manner, especially after PH. Proliferation of hepatocytes, as indicated by BrdU labelling indices (LI), was higher in GST-P+ foci than in surrounding hepatocytes in all 2-AAF-treated groups, even after cessation of carcinogen administration. Proliferative response of hepatocytes to PH was delayed in rats treated with the highest dose of 2-AAF in both foci and in surrounding areas possibly due to the 2-AAF toxicity. In the PB treated group, the results were similar to those for the lower dose 2-AAF-treated groups. It is concluded that the development of GST-P+ foci and cell proliferation in GST-P+ foci are directly related to 2-AAF treatment in a dose-dependent manner and the present assay system is reliable for detection of carcinogenicity of chemicals even at low doses.
Carcinogenesis 1991 Jun
PMID:Dose-dependent effects of 2-acetylaminofluorene on hepatic foci development and cell proliferation in rats. 204 5

The mechanism(s) by which a diet devoid of choline (CD) induces hepatocellular carcinomas in rats remains unknown. Although animals fed this diet develop nuclear lipid peroxidation, suggesting oxidative DNA damage, there is no direct evidence that this occurs. In this study, 8-hydroxydeoxyguanosine (8-OHdG), a DNA adduct generated by reactive oxygen species, was analyzed in the liver of rats fed a CD diet and in controls receiving a choline-sufficient (CS) diet. After partial hepatectomy, the animals were injected with diethylnitrosamine (DEN, 50 mg/kg body wt) or with saline and fed a CD or CS diet for 24 weeks. While liver DNA from rats injected either with DEN or saline and fed a CS diet did not show detectable amounts of the nucleotide, those who were fed DEN/CD and saline/CD demonstrated similar, easily measurable levels of 8-OHdG. These results indicate that there is a positive association between the continuous administration of a CD diet and the production of 8-OHdG in liver DNA, and support the idea that oxidative DNA damage is involved in carcinogenesis by a CD diet.
Carcinogenesis 1990 Oct
PMID:Is 8-hydroxydeoxyguanosine a mediator of carcinogenesis by a choline-devoid diet in the rat liver? 220 1

Transgenic mice containing one copy of hepatitis B virus (HBV) genome without the core gene and expressing hepatitis B surface antigen (HBsAg) were crossed with C3H/He mice. The F1 hybrids (approximately 50% HBV positive and approximately 50% HBV negative) were treated with a single dose of diethylnitrosamine (NDEA) or p-dimethylaminoazobenzene (DAB) given at 7 days of age, or were untreated. Mice were kept under observation without further treatments until 30 weeks old and then killed. Stereological analysis of liver nodules and estimations of their size distribution demonstrated a significative enhancing effect of HBV transgene in both NDEA- and DAB-induced hepatocarcinogenesis in male mice. Hepatocellular adenomas and carcinomas were also more frequent in NDEA-treated HBV-positive than HBV-negative male mice. Female mice showed a lower tumorigenic response than males without significant differences between groups of HBV-positive and HBV-negative mice. It is proposed that the presence of the transgene enhanced carcinogen-induced hepatocarcinogenesis.
Carcinogenesis 1990 Jun
PMID:Transgenic mice containing hepatitis B virus sequences are more susceptible to carcinogen-induced hepatocarcinogenesis. 234 70

Consequences on mutation induction of a defective excision repair (exr-) system have been studied in Drosophila for a series of 30 carcinogens, representing 17 mono-, six bi- or trifunctional agents, five cyclic alkylating agents and two polycyclic aromatic compounds. Repair-inactive spermatozoa or (late) spermatids were mutagenized and then transferred to excision-defective (mei-9L1) or appropriate excision proficient (exr+) oocytes. Hypermutability responses in exr- in relation to the exr+ genotype were determined by calculating frep-/frep- (ratio = y) indices at x = 1% X-linked recessive lethal mutations (SLRL); frep- denotes induced SLRL frequency in mei-9L1, frep+ that induced in repair-proficient condition, and x = 1 means 1% SLRL in exr+, A linear positive relationship between frep-/frep+ estimates and nucleophilic selectivity (Swain and Scott's constants s) was established for 18 carcinogens, representing either mono- and cyclic alkylating agents: frep-/frep+ = 12.4s - 1.9; r = 0.79, r2 = 0.62, P less than 0.01 Noticeable exceptions to this linear correlation indicated that, although nucleophilicity is a principle determinator for hypermutability response in exr- mutants, other cellular factors play a significant role as well. These are (i) the faster rate of removal of methyl adducts compared to ethyl derivatives, (ii) the complex metabolism of some of the carcinogens (PC, DTIC, DMPT, Cl3DMPT) and (iii) the length of the time period between DNA modification and onset of replication after fertilization. By contrast, CEO and polyfunctional agents (FA, HMPA, MC, MCT, Thio-TEPA and BCNU) did not follow the linear relationship. They provided lower frep-/frep+ indices than would be anticipated on the basis of their nucleophilic selectivity (MC, BCNU, Thio-TEPA) or were even inactive (FA, MCT, HMPA) in the Drosophila repair assay. Both in terms of consistency (mono- and cyclic alkylating agents) and exceptional behavior (CEO, the six crosslinking agents), there is an intriguing positive correlation between relative efficiency ranking of carcinogens and with respect to their position on the potency scale for hypermutability. Thus, in genetic terms, as most potent carcinogens in rodents appear to be those agents giving no effect or a low activity in the exr- genotype in Drosophila: carcinogens with high potential for direct miscoding [ENU, ENNG, DEN, iPMS, CEO and presumably DMBA (?)], and those capable of forming crosslinks (MC, MCT, HMPA, Thio-TEPA and BCNU).
Carcinogenesis 1989 Nov
PMID:Nucleophilic selectivity of carcinogens as a determinant of enhanced mutational response in excision repair-defective strains in Drosophila: effects of 30 carcinogens. 250 91

Two structurally unrelated compounds, 1,1'-(2,2,2-trichloroethylidene) bis(4-chlorobenzene) (DDT) and 12-O-tetradecanoylphorbol-13-acetate (TPA), are both potent inhibitors of cell-cell communication in vitro as well as tumour promoters in vivo. There is evidence that TPA acts via a specific receptor mechanism involving activation of protein kinase C (pkC). The mechanism of action of DDT has been discussed in terms of membrane perturbation, increased intracellular calcium, interaction with calmodulin and decreased cAMP levels. In the present study the objective was to examine the potential role of pkC activation in DDT-induced inhibition of intercellular communication in cultured cells. The V79 metabolic cooperation assay was used for measuring intercellular communication. Furthermore, the effects of DDT on the activity of partially purified pkC from V79 cells was measured, as was the interaction of DDT with the phorbol ester/DAG-binding site on the pkC enzyme. Results from the biochemical studies showed that DDT neither activates pkC nor binds to the phorbol ester/DAG-binding site, as measured by displacement of PDBU binding. Using the metabolic cooperation assay it was demonstrated that pretreatment with TPA made cells refractory, i.e. a second application of TPA did not inhibit cell-cell communication. DDT added to cells down-regulated with TPA inhibited cell-cell communication, even though these cells were refractive to TPA. This result further supports the hypothesis that DDT and TPA inhibit intercellular communication primarily by different pathways. At non-cytotoxic concentrations, pkC inhibitors (H7, W7 and palmitoyl carnitine) did not affect the TPA- or DDT-induced inhibition of cell-cell communication in the V79 metabolic cooperation assay. Quercetin, a pkC inhibitor which has been reported to eliminate DDT- or TPA-induced inhibition of intercellular communication, was investigated in an in vivo study that measured promotion of enzyme-altered foci in DEN-treated rat liver. Quercetin co-administered with DDT did not act as an antipromoter.
Carcinogenesis 1989 Mar
PMID:Mechanistic studies on the DDT-induced inhibition of intercellular communication. 256 19

We have recently reported that the tobacco-related nitrosamines N-nitrosodiethylamine (DEN) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) stimulate cell proliferation in cell lines derived from human neuroendocrine carcinoma and adenocarcinoma (comprised of Clara cells) of the lung. In the neuroendocrine cell line, this effect was inhibited by antagonists of nicotinic cholinergic receptors which regulate the secretion of peptide hormones and cell proliferation of pulmonary neuroendocrine cells. No such inhibition was observed in the adenocarcinoma line. Clara cells reportedly do not have acetylcholine receptors and secretion of this cell type is regulated by beta-adrenergic receptors instead. In this experiment, we test the hypothesis that the latter types of receptors are involved in the regulation of cell growth of normal and nitrosamine-stimulated adenocarcinoma cells with features of Clara cells. Our data demonstrate a pronounced stimulation of cell growth by the beta-adrenergic agonist isoproterenol, DEN and NNK, as well as a dose-dependent inhibition of such growth-stimulating effects by the beta-adrenergic antagonist propranolol. These findings suggest an important role of beta-adrenergic receptors in the regulation of cell proliferation in lung tumors comprised of this cell type.
Carcinogenesis 1989 Sep
PMID:Regulation of cell proliferation by beta-adrenergic receptors in a human lung adenocarcinoma cell line. 256 45

The tumor-promoting ability of clonazepam (CZP), a widely used benzodiazepine anticonvulsant, was investigated in an in vivo mouse liver tumor promotion assay and an in vitro mouse hepatocyte intercellular communication assay. The development of preneoplastic hepatocellular foci of cellular alteration and hepatocellular neoplasms was studied in male B6C3F1 mice initiated, at 5 weeks of age, with a single i.p. injection of N-nitrosodiethylamine (NDEA; 90 mg/kg body weight) in tricaprylin, followed by administration of either phenobarbital (PB; 0.05%) or CZP (0.068% or 0.136%) in diet beginning 2 weeks after carcinogen injection and continuing to 60 weeks of age. Several mice from each group were killed after 9, 21, 33 or 53 weeks on test diet, and portions of liver and other organs were fixed in formalin and examined histologically. Unlike PB, CZP did not promote the development of preneoplastic hepatocellular foci or neoplasms (adenomas and carcinomas) in NDEA-initiated mice. Following limited (2 weeks) dietary exposure at 0.15%, CZP was a potent inducer of hepatic P450IIB1-mediated alkoxyresorufin O-dealkylase activities. In contrast, the degree of induction in hepatic tissue from mice fed 0.136% CZP for 53 weeks was markedly lower than that in mice fed 0.05% PB for 53 weeks. In the in vitro assay, diazepam, a strong tumor promoter in mouse liver, significantly inhibited mouse hepatocyte gap junctional intercellular communication, while CZP had no significant effect on this parameter. Thus, CZP, a drug structurally related to diazepam, is inactive as a liver tumor promoter in mice.
Carcinogenesis 1989 Sep
PMID:Lack of promoting effect of clonazepam on the development of N-nitrosodiethylamine-initiated hepatocellular tumors in mice is correlated with its inability to inhibit cell-to-cell communication in mouse hepatocytes. 276 64

Patients with hepatic tumours have increased serum activities of alkaline phosphatases. In order to clarify the origin of the increased enzyme activity, two experimental models of rat liver carcinogenesis were studied. In one model, the resistant hepatocyte model, the process was initiated by diethylnitrosamine (DEN, 200 mg/kg), and preneoplastic liver nodules were selected for by 2 weeks of 2-acetylaminofluorene (2-AAF, 0.02%) feeding and partial hepatectomy (PH). High activities of serum alkaline phosphatases were found in these rapidly growing nodules harvested at the peak time of nodular mass expansion. In the other model in which nodules were induced with long-term intermittent feeding of a diet containing 0.05% 2-AAF and harvested in a late stage with a low increase of nodular liver cell mass, no such increase in serum alkaline phosphatase activity was found. A similar difference was also noted when measuring the activities of the enzyme in the nodular tissue. Thus the first model showed high activities of the enzyme in the nodular tissue, while the second model had similar activities to those of the control animals. The serum levels reflected the nodular enzyme activity in both models. The tissue surrounding the nodules did not show increased enzyme activity. No difference was noted in the serum or tissue activity of transaminases. In both models the liver nodules occupied 30-50% of the liver volume. The experimental models were selected to emphasize the importance of the rate of intrahepatic mass expansion for the levels of serum alkaline phosphatase activities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The source of serum alkaline phosphatases in liver-tumour-bearing rats. 277 Apr 34


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